title: Inhibition of telomerase recruitment and cancer cell death.
abstract: Continued proliferation of human cells requires maintenance of telomere length, usually accomplished by telomerase. Telomerase is recruited to chromosome ends by interaction with a patch of amino acids (the TEL patch, for TPP1 glutamate (E) and leucine (L)-rich patch) on the surface of telomere protein TPP1. In previous studies, interruption of this interaction by mutation prevented telomere extension in HeLa cells, but the cell culture continued to grow. We now show that the telomerase inhibitor BIBR1532 acts together with TEL patch mutations to inhibit the growth of HeLa cell lines and that apoptosis is a prominent mechanism of death of these cells. Survivor cells take over the population beginning around 40 days in culture. These cells no longer express the TEL patch mutant TPP1, apparently because of silencing of the expression cassette, a survival mechanism that would not be available to cancer cells. These results provide hope that inhibiting the binding of telomerase to the TEL patch of TPP1, perhaps together with a modest inhibition of the telomerase enzyme, could comprise an effective anticancer therapy for the ∼90% of human tumors that are telomerase-positive.
authors.affiliation: From the Howard Hughes Medical Institute.
authors.forename: Mai
authors.initials: M
authors.lastname: Nakashima
authors.forename: Jayakrishnan
authors.initials: J
authors.lastname: Nandakumar
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Sullivan
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Espinosa
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cech
mesh_terms: D062365:Aminobenzoates / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D009281:Naphthalenes / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism; D000089804:Shelterin Complex; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034501:Telomere-Binding Proteins
chemical_list: C495876:ACD protein, human; D062365:Aminobenzoates; C458523:BIBR 1532; D009281:Naphthalenes; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D019098:Telomerase; D057057:Serine Proteases
keywords: Apoptosis; Cancer; Cell Biology; TPP1; Telomerase; Telomeres